WO2010118921A1 - Nouveaux antagonistes de p2x7r et leur utilisation - Google Patents
Nouveaux antagonistes de p2x7r et leur utilisation Download PDFInfo
- Publication number
- WO2010118921A1 WO2010118921A1 PCT/EP2010/053097 EP2010053097W WO2010118921A1 WO 2010118921 A1 WO2010118921 A1 WO 2010118921A1 EP 2010053097 W EP2010053097 W EP 2010053097W WO 2010118921 A1 WO2010118921 A1 WO 2010118921A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- indol
- bromo
- chloro
- hydroxypropyl
- acetamide
- Prior art date
Links
- 0 *CC(NC1c2*(*)c(*)*(*)*(*)c2N(*)*1)=N Chemical compound *CC(NC1c2*(*)c(*)*(*)*(*)c2N(*)*1)=N 0.000 description 1
- YXCLCFKUJGINNC-UHFFFAOYSA-N CC(C[n]1c2cccc(Br)c2c(NC(CCC2CCCCC2)=O)c1)O Chemical compound CC(C[n]1c2cccc(Br)c2c(NC(CCC2CCCCC2)=O)c1)O YXCLCFKUJGINNC-UHFFFAOYSA-N 0.000 description 1
- SFONSAAWBCIDER-UHFFFAOYSA-N CC(C[n]1c2cccc(Cl)c2c(NC(CCC2CCCCCC2)=O)c1)O Chemical compound CC(C[n]1c2cccc(Cl)c2c(NC(CCC2CCCCCC2)=O)c1)O SFONSAAWBCIDER-UHFFFAOYSA-N 0.000 description 1
- RURAJWCFGSAIHX-UHFFFAOYSA-N CNCC(C[n]1c2cccc(Br)c2c(NC(CC2CCCCCC2)=O)c1)O Chemical compound CNCC(C[n]1c2cccc(Br)c2c(NC(CC2CCCCCC2)=O)c1)O RURAJWCFGSAIHX-UHFFFAOYSA-N 0.000 description 1
- NDWPJXLFSZNCQI-UHFFFAOYSA-N OCC[n]1c2cccc(Cl)c2c(NC(CC2CCCCCC2)=O)c1 Chemical compound OCC[n]1c2cccc(Cl)c2c(NC(CC2CCCCCC2)=O)c1 NDWPJXLFSZNCQI-UHFFFAOYSA-N 0.000 description 1
- KIBHKUGEPGLFND-UHFFFAOYSA-N OCC[n]1c2cccc(Cl)c2c(NC(CCC2CCCCC2)=O)c1 Chemical compound OCC[n]1c2cccc(Cl)c2c(NC(CCC2CCCCC2)=O)c1 KIBHKUGEPGLFND-UHFFFAOYSA-N 0.000 description 1
- YAQUKGTUOXFJJQ-UHFFFAOYSA-N OCC[n]1c2nccc(Br)c2c(NC(CC2CCCCCC2)=O)c1 Chemical compound OCC[n]1c2nccc(Br)c2c(NC(CC2CCCCCC2)=O)c1 YAQUKGTUOXFJJQ-UHFFFAOYSA-N 0.000 description 1
- BLKOCKLQWITSNZ-UHFFFAOYSA-N [BH+]c1c(c(NC(CCC2CCCCCC2)=N)c[n]2CCO)c2ccc1 Chemical compound [BH+]c1c(c(NC(CCC2CCCCCC2)=N)c[n]2CCO)c2ccc1 BLKOCKLQWITSNZ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
Definitions
- the present application relates to novel P2X7R antagonists that are N-indol-3-yl- acetamide and N-azaindol-3-yl-acetamide compounds, pharmaceutical compositions comprising these compounds and to their use in the prophylactic and therapeutic treatment of diseases and disorders mediated by P2X7R.
- P2X7R is an ATP-gated ion channel belonging to the P2X ionotropic channel family.
- the gene was first isolated from rat brain (Surprenant et al. (1996) 272:735-738) and subsequently from a human monocyte library (Rassendren et al. (1997) J. Biol. Chem. 272:5482-5486; Genbank accession numbers NM_002562, Y09561) by virtue of its sequence homology with the other members of the P2X family. It was later found that P2X7R corresponded to the unidentified P2Z receptor which mediates the permeabilising action of ATP on mast cells and macrophages (Dahlqvist and Diamant (1974) Acta Physiol.
- the P2X7R has two hydrophobic membrane-spanning domains, an extracellular loop, and forms transmembrane ion channels. P2X7R bears a pharmacological profile markedly different from other P2X homo- or heteromers (North and Surprenant (2000) Annual Rev. Pharmacology Toxicology 40:563-580). P2X7R requires levels of ATP in excess of 1 mSvi to achieve activation, whereas other P2X receptors activate at ATP concentrations of ⁇ 100 ⁇ M (Steinberg et al. (1987) J.
- P2X7R is expressed in haematopoietic cells, mast cells, lymphocytes, erythrocytes, fibroblast, Langerhans cells, and macrophages (Surprenant et al., 1996, Science 272:3118-3122).
- P2X7R is involved in the regulation of the immune function and inflammatory response. Activation of P2X7R by ATP in macrophages is associated with mitogenic stimulation of T cells (Baricordi et al. (1996) Blood 87:682-690), the release of cytokines (Griffiths et al. (1995) J. Immol. 154:2821-2828), and formation of macrophage polykarions (Falzoni et al. (1995) J. Clin. Invest. 95:1207-1216).
- P2X7R is involved in the processing and release of active interleukin-1beta (IL-1 ⁇ ) from proinflammatory cells (Perregaux and Gabel (1998) J Biol Chem 269:15195-15203; Ferrari et al., (2006) J Immunol 176: 3877-3883). Stimulation of the P2X7R by ATP can also result in apoptosis and cell death by triggering the formation of non-selective plasma membrane pores (Di Virgilio et al. (1998) Cell Death Differ. 5:191-199).
- IL-1beta active interleukin-1beta
- P2X7R Upregulation of P2X7R has been observed during ischemic damage and necrosis induced by occlusion of middle cerebral artery in rat brain (CoIIo et al. (1997) Neuropharmacol 36:1277-1283). Recent studies indicate a role of P2X7R in the generation of superoxide in microglia, and upregulation of P2X7R has been detected around amyloid plaques in a transgenic mouse models for Alzheimer's disease (Parvathenani et al. (2003) J Biol Chem 278:13300-13317) and in multiple sclerosis lesions from autopsy brain sections (Narclsse et al. (2005) GIIa, 49:245-258).
- adamantane derivatives WO 99/29660, WO 99/29661 , WO 00/61569, WO 01/42194, WO 01/44170, WO 01/44213, WO 01/94338, WO 03/041707, WO 03/042190, WO 03/080579, WO 04/074224, WO 05/014529, WO 06/025783, WO 06/059945), piperidine and piperazine compounds (WO 01/44213, WO 01/46200, WO 08/005368), benzamide and heteroarylamide compounds (WO 03/042191 , WO 04/058731 , WO 04/058270, WO 04/099146, WO 05/019182, WO 06/003500, WO 06/003513, WO 06/067444), substituted tyrosine derivatives (WO 00/71529, WO 03/047515,
- the object on the present invention is to provide a novel series of compound which can inhibit P2X7R activity and can be used in the treatment of the above mentioned diseases.
- the present invention relates to novel P2X7R antagonists that are N-indol-3-yl- acetamide and N-azaindol-3-yl-acetamide compounds represented by the general formula (I):
- Ri is a mono- or bicycloalkylalkyl group or mono- or bicycloalky! group
- R 2 is selected from straight or branched CrC 5 alkyl which may optionally substituted with -OH, -CH 2 -OH, C1-C5 alkoxy, NH2-, N(R a )2- , NHR 3 -, CN-, CF3, halogen (i.e.
- R 3 is C-j-C-s alkyl
- R3, R 4 , R5, R ⁇ are at eac ⁇ occurrence independently selected from hydrogen, halogen (i.e. Cl, F, Br or I), methyl, methoxy, cyano, or trifluoromethyl;
- a, b, c, d, x are at each occurrence independently selected from carbon, or nitrogen; or a pharmaceutically acceptable salt or solvate thereof (whereby x must have a hydrogen substituent if it is carbon).
- R ⁇ is a group selected from cyciopentyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl, cycloheptyl, cycloheptylmethyl, bicyclo[2.2.2]octan-1-yl and bicyclo[2.2.2]octan-1- yimethyl are preferred.
- R 2 is substituted with one or two substituents selected from -OH, -CH 2 -OH, d-C 5 alkoxy, -NH 2 , NHRa, -CN, -CF 3 , halogen, piperidino, morpholino, pyrrolidino or 5H-tetrazolylpropyl.
- R2 is C1-C5 alkyl or C 2 -C 5 hydroxyalkyl are also preferred.
- R3, R4, R5 and RQ are hydrogen. If necessitated by valency, R 3 -R 6 may also be absent.
- a, b, c, and d are C or one of a, b, c and d is N.
- the invention further relates to a compound of Formula (i) or a pharmaceutically acceptable salt or solvate thereof, being:
- the present invention also includes isotopically-labelled compounds, which are identical to those recited in Formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass 25 number usually found in nature.
- isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 35 CI, respectively.
- isotopically-labelled compounds of the present invention for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2 H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
- Isotopically-labelled compounds of Formula (I) of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Examples below, by substituting a readily available isotopically- labelled reagent for a non- isotopicaliy-labelled reagent.
- Pharmaceutically acceptable salts include those formed with anions such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with cations such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine and procaine.
- the present application is directed to a pharmaceutical composition comprising a compound of Formula (I) of the present invention.
- composition according to the present invention may further comprise an additional active compound in separate or unit dosage form for simultaneous or sequential administration.
- the compounds of Formula (!) or a pharmaceutically acceptable salt thereof can be used in the manufacture of a medicament for the prophylactic or therapeutic treatment of any disease state in a human, or other mammal, which is exacerbated or caused by excessive or unregulated cytokine production by such mammal's cells, such as but not limited to monocytes and/or macrophages.
- the present invention also relates to the treatment of an IL- 1 or cytokine mediated condition.
- an "IL- 1 mediated condition” and “cytokine mediated condition” includes, but is not limited to, a disease or disorder selected from the group consisting of arthritis (including psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and acute synovitis), inflammatory bowel disease, Crohn's disease, emphysema, acute respiratory distress syndrome, adult respiratory distress syndrome, asthma, bronchitis chronic obstructive pulmonary disease, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, allergic reactions, allergic contact hypersensitivity, eczema, contact dermatitis, psoriasis, sunburn, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, bone resorption disease, loosening
- arthritis
- the present invention relates to a pharmaceutical composition for the treatment of an IL- 1 mediated condition in a mammal, including a human, comprising an amount of a compound of Formula (I), effective in treating such a condition and a pharmaceutically acceptable carrier.
- the compounds of the invention are useful for the treatment of rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic obstructive pulmonary disease (COPD), hyperresponsiveness of the airway, septic shock, glomerulonephritis, irritable bowel disease, Crohn's disease, ulcerative colitis, atherosclerosis, growth and metastases of malignant cells, myoblastic leukemia, diabetes, Alzheimer's disease, meningitis, osteoporosis, burn injury, ischemic heart disease, stroke and varicose veins.
- COPD chronic obstructive pulmonary disease
- the invention further provides a pharmaceutical composition for treating osteoarthritis which comprises a therapeutically effective amount of a compound of Formula (!), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined.
- the invention further provides a pharmaceutical composition for effecting immunosuppression (e. g. in the treatment of rheumatoid arthritis, irritable bowel disease, atherosclerosis or psoriasis) which comprises a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined.
- a pharmaceutical composition for effecting immunosuppression e. g. in the treatment of rheumatoid arthritis, irritable bowel disease, atherosclerosis or psoriasis
- a pharmaceutical composition for effecting immunosuppression e. g. in the treatment of rheumatoid arthritis, irritable bowel disease, atherosclerosis or psoriasis
- a pharmaceutical composition for effecting immunosuppression e. g. in the treatment of rheumatoid arthritis, irritable bowel disease, atherosclerosis or psoriasis
- the invention also provides a pharmaceutical composition for treating an obstructive airways disease (e.g. asthma or COPD) which comprises a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined.
- an obstructive airways disease e.g. asthma or COPD
- a pharmaceutical composition for treating an obstructive airways disease which comprises a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined.
- the present invention yet further provides a pharmaceutical composition for treating a mammal susceptible to or afflicted with conditions that are causally related to abnormal activity of the P2X7 receptor, such as neurodegenerative diseases and disorders including, for example, Parkinson's disease, multiple sclerosis, glaucoma, age-related macular degeneration, uveitis, neuropathic pain, diseases and disorders which are mediated by or result in neuromfiammation such as, for example traumatic brain injury and encephalitis; centrally-mediated neuropsychiatric diseases and disorders such as, for example depression mania, bipolar disease, anxiety, schizophrenia, eating disorders, sleep disorders and cognition disorders, epilepsy and seizure disorders comprising a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined.
- neurodegenerative diseases and disorders including, for example, Parkinson's disease, multiple sclerosis, glaucoma, age-related macular degeneration, uveitis, neuropathic
- the pharmaceutical composition according to the present invention may be used for the treatment of affective disorders.
- the affective disorder is selected from depression, anxiety, bipolar disorder and schizophrenia.
- the pharmaceutical composition according to the present invention is useful for the treatment of neurodegenerative diseases and disorders, diseases and disorders which are mediated by or result in neuroinfiammation and centrally-mediated neuropsychiatric diseases and disorders.
- composition according to the present invention may particuiary be useful for the treatment of pain, inflammatory processes, and degenerative conditions.
- the inflammatory process is selected from rheumatoid arthritis, osteoporosis and chronic obstructive pulmonary disease.
- composition according to the present invention may be used for the treatment of neuropathic pain.
- Dosage, pharmaceutical preparation and delivery of a compound of Formula (I) for use in accordance with the present invention can be formulated in conventional manner according to methods found in the art, using one or more physiological carriers or excipient, see, for example Ansel et al., "Pharmaceutical Dosage Forms and Drug Delivery Systems", 7th edition, Lippincott Williams & Wilkins Publishers, 1999.
- the P2X7R modulating agent and its physiologically acceptable salts and solvates can be formulated for administration by inhalation, insufflation (either through the mouth, or nose), oral, buccal, parenteral, or rectal administration.
- the pharmaceutical composition of a compound of Formula (I) can take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutical acceptable excipients such as binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone, hydroxypropyl methylcellulose), fillers (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate), lubricants (e.g., magnesium stearate, talc, silica), disintegrants (e.g., potato starch, sodium starch glycolate), or wetting agents (e.g., sodium lauryl sulphate).
- binding agents e.g., pregelatinised maize starch, polyvinylpyrrolidone, hydroxypropyl methylcellulose
- fillers e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate
- lubricants e.g., magnesium stearate, talc, silica
- disintegrants e
- the term "pharmaceutically acceptable” means approved by a regulatory agency or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.
- carrier refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered.
- Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
- Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium ion, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
- the composition if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can be in the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like.
- the composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides.
- Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by E. W. Martin. Such compositions will contain a therapeutically effective amount of the aforementioned compounds, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation should suit the mode of administration.
- Liquid preparations for oral administration can be in the form of, for example, solutions, syrups, or suspensions, or can be presented as a dry product for constitution with water or other suitable vehicle before use.
- Such liquid preparation can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol, syrup, cellulose derivatives, hydrogenated edible fats), emulsifying agents (e.g., lecithin, acacia), non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, fractionated vegetable oils), preservatives (e.g., methyl or propyl-p-hydroxycarbonates, soric acids).
- suspending agents e.g., sorbitol, syrup, cellulose derivatives, hydrogenated edible fats
- emulsifying agents e.g., lecithin, acacia
- non-aqueous vehicles e.g., almond oil, oily esters, ethyl
- a compound of Formula (I) of the present invention is conveniently delivered in the form of an aerosol spray presentation from a pressurised pack or a nebulizer, with the use of a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas).
- a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
- the dosage unit can be determined by providing a valve to deliver a metered amount.
- Capsules and cartridges of, for example, gelatine, for use in an inhaler or insufflator can be formulated containing a powder mix of a compound of Formula (!) and a suitable powder base such as lactose or starch.
- a compound of Formula (I) of the present invention can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion.
- Site of injections include intra-venous, intra-peritoneal or sub-cutaneous.
- Formulations for injection can be presented in units dosage form (e.g., in phial, in multi-dose container), and with an added preservative.
- a compound of Formula (I) of the present invention can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing, or dispersing agents.
- the agent can be in powder form for constitution with a suitable vehicle (e.g., sterile pyrogen-free water) before use.
- compositions for intravenous administration are solutions in sterile isotonic aqueous buffer.
- the composition can also include a solubilizing agent and a local anesthetic such as lignocaine to ease pain at the site of the injection.
- the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilised powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent.
- the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline.
- an ampoule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.
- a compound of Formula (I) of the present invention can be formulated for transdermal administration.
- Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
- the active ingredients When formulated as a ointment, the active ingredients will typically be combined with either a paraffinic or a water- miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base.
- transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope of this invention.
- the compounds of this invention can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.
- composition of the invention can be formulated as neutral or sait forms.
- Pharmaceutically acceptable salts include those formed with anions such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with cations such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, etc.
- a compound of Formula (I) of the present invention can also, if desired, be presented in a pack, or dispenser device which cancontain one or more unit dosage forms containing the said agent.
- the pack can for example comprise metal or plastic foil, such as blister pack.
- the pack or dispenser device can be accompanied with instruction for administration.
- a compound of Formula (I) of the present invention can be administered as sole active agent or can be adminstered in combination with other agents.
- agents include non-steroidal anti-inflammatory drug (NSAIDS) such as celecoxib, rofecoxib, cimicoxib, etoricoxib, lumiracoxib, valdecoxib, deracoxib, N-(2- cyclohexyloxynitropheny!methane sulphonamide, COX189, ABT963, JTE-522, GW- 406381 , LAS-34475, CS-706, PAC-10649, SVT-2016, GW-644784, tenidap, acetylsaljcylic acid (aspirin), amoxiprin, benorilate, choline magnesium salicylate, diflunisal, urgencylamine, methyl salicylate, magnesium salicylate, salicyl salicylate (salsalatee), diclofenac, aceclofe
- a compound of Formula (I) of the present invention can be combined with agents such as TNF- ⁇ inhibitors such as anti-TNF monoclonal antibodies (such as Remicade, CDP-870 and D2E7) and TNF receptor immunoglobulin molecules (such as Enbrel), low dose methotrexate, lefunomide; ciclesonide; hydroxychloroquine, d- penicillamine, auranofin or parenteral or oral gold.
- TNF- ⁇ inhibitors such as anti-TNF monoclonal antibodies (such as Remicade, CDP-870 and D2E7) and TNF receptor immunoglobulin molecules (such as Enbrel), low dose methotrexate, lefunomide; ciclesonide; hydroxychloroquine, d- penicillamine, auranofin or parenteral or oral gold.
- a compound of Formula (!) of the present invention can aiso be administered in combination with an inhibitor of proTNFalpha convertase enzyme (TACE) such as 3- Amino-N-hydroxy- ⁇ -(2-methylpropyl)-3-[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]-2- oxo-1 -pyrrolidineacetamide, 2(S),3(S)-Piperidinedicarboxamide, N3-hydroxy-1- methyl-N-2-[4-[(2-methyl-4-quinolinyl)methoxy]pheny!], 3-
- TACE proTNFalpha convertase enzyme
- Thiomorpholinecarboxamide 4-[[4-(2-butynyloxy)phenyl]sulfonyl]-N-hydroxy-2,2- dimethyl, 5-Hexenoic acid, 3-[(hydroxyamino)carbonyl]-2-(2-methylpropyl)-6-phenyl-, 2-(2-methylpropyl)-2-(methylsulfonyl)hydrazide, (2R,3S,5E), 2-
- Benzamide N-(2,4-dioxo-1 ,3,7-triazaspiro[4.4]non-9-yl)-4-[(2-methyl-4- quinolinyl)methoxy]
- Benzamide N-[(1 -acetyl-4-piperidinyl)(2,5-dioxo-4- imidazolidinyl)methyl]-4-[(2-meth- yl-4-quinolinyl)methoxy]
- 2,4-Smidazolidinedione 5-methyl-5-[[4-[(2-methyl-4-quinolinyi)methoxy]phenyl]sulfonyl]methyl].
- TACE inhibitors are described in WO 99/18074, WO 99/65867, U.S. Pat. No. 6,225,311 , WO 00/00465, WO 00/09485, WO 98/38179, WO 02/18326, WO 02/096426, WO 03/079986, WO 03/055856, WO 03/053941 , WO 03/040103, WO 03/031431 , WO 03/024899, WO 03/016248, WO 04/096206, WO 04/033632, WO 04/108086, WO 04/043349, WO 04/032846, WO 04/012663, WO 04/006925, WO 07/016597.
- a compound of Formula (I) of the present invention can also be administered in combination with a corticosteroid such as budesonide, corticosterone, Cortisol, cortisone acetate, prednisone, prednisolone, methyiprednisolone, dexamethasone, betamethasone, triamcinolone, beclometasone, fludrocortisone acetate, deoxycorticosterone acetate (doca), aldosterone.
- a corticosteroid such as budesonide, corticosterone, Cortisol, cortisone acetate, prednisone, prednisolone, methyiprednisolone, dexamethasone, betamethasone, triamcinolone, beclometasone, fludrocortisone acetate, deoxycorticosterone acetate (doca), aldosterone.
- a compound of Formula (I) of the present invention can further be administered in combination with a ⁇ 2-adrenergic receptor agonist such as formoterol, salbutamol (albuterol), levalbuterol, terbutaiine, pirbuterol, procaterol, metaproterenoi, fenoteroi, bitolterol mesylate, salmeterol, bambuterol, clenbuterol.
- a ⁇ 2-adrenergic receptor agonist such as formoterol, salbutamol (albuterol), levalbuterol, terbutaiine, pirbuterol, procaterol, metaproterenoi, fenoteroi, bitolterol mesylate, salmeterol, bambuterol, clenbuterol.
- a compound of Formula (I) of the present invention can further be administered in combination with an antidepressant drug such as sertraline, escitalopram, fluoxetine, bupropion, paroxetine, venlafaxine, trazodone, amitriptyline, citaiopram, duioxetine, mirtazapine, nortriptyline, imipramine, lithium.
- an antidepressant drug such as sertraline, escitalopram, fluoxetine, bupropion, paroxetine, venlafaxine, trazodone, amitriptyline, citaiopram, duioxetine, mirtazapine, nortriptyline, imipramine, lithium.
- a compound of Formula (I) of the present invention can further be administered in combination with an antipsychotic drug such as chiorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, mesoridazine, promazine, triflupromazine, levomepromazine, promethazine, chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, haloperidol, droperidoi, pimozide, melperone, benperidol, triperidol, clozapine , olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, paliperidone , bifeprunox, aripiprazoie.
- an antipsychotic drug such as chiorpromazine, fluphenazine, perphenazine, prochlor
- a compound of Formula (I) of the present invention can also be administered in combination with a leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist, for example, z ⁇ euton; ABT- 761 ; fenleuton; tepoxalin; nicaraven; VIA-2291 ; etaiocib; ketoprofen, Abt-79175; Abt- 85761 ; N-(5-substituted) thiophene-2-alkyisulfonamides; TDT-070; licofeione; PEP- 03; tenoxicam; 2,6-di-tert-butyiphenol hydrazones; methoxytetrahydropyrans such as Zeneca ZD-2138; the compound SB- 210661 ; pyridinyl-substituted 2- cyanonaphthalene compounds such as
- a compound of Formula (1) of the present invention can be administered in combination with a receptor antagonists for ieukotrienes LTB4, LTC4, LTD4, and LTE, for example, phenothiazin-3-ones such as L-651 ,392; amidino compounds such as CGS-25019c; benzoxaiamines such as ontezolast; benzenecarboximidamides such as BHL 284/260; and compounds such as zafirlukast, ablukast, montelukast, praniukast, verlukast (MK-679), RG-12525, Ro-245913, iraiukast (CGP 45715A), and BAY x 7195; masilukast.
- a receptor antagonists for ieukotrienes LTB4, LTC4, LTD4, and LTE for example, phenothiazin-3-ones such as L-651 ,392; amidino compounds such
- a compound of Formula (I) of the present invention can also be administered in combination with a PDE4 inhibitor including inhibitors of the isoform PDE4D.
- a compound of Formula (I) of the present invention can also be administered in combination with a antihistaminic Hi receptor antagonists including cetirizine, loratadine, desioratadine, fexofenadine, astemizole, azelastine, and chlorpheniramine.
- a antihistaminic Hi receptor antagonists including cetirizine, loratadine, desioratadine, fexofenadine, astemizole, azelastine, and chlorpheniramine.
- a compound of Formula (!) of the present invention can further be administered in combination with with a gastroprotective H 2 receptor antagonist.
- a compound of Formula (I) of the present invention can yet further be administered in combination with an ⁇ 1- and ⁇ 2-adrenoceptor agonist vasoconstrictor sympathomimetic agent, including propylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoiine hydrochloride, tetrahydrozoline hydrochloride, xylometazoiine hydrochloride, and ethylnorepinephrine hydrochloride.
- an ⁇ 1- and ⁇ 2-adrenoceptor agonist vasoconstrictor sympathomimetic agent including propylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoiine hydrochloride, tetrahydrozoline hydrochloride, xylometazoiine
- a compound of Formula (I) of the present invention can be administered in combination with anticholinergic agents including ipratropium bromide; tiotropium bromide; oxitropium bromide; pirenzepine; and telenzepine
- anticholinergic agents including ipratropium bromide; tiotropium bromide; oxitropium bromide; pirenzepine; and telenzepine
- the present invention still further relates to the combination of a compound of the invention together with a ⁇ r to ⁇ 4 -adrenoceptor agonists including metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, and pirbuterol; or methylxanthanines including theophylline and aminophyliine; sodium cromoglycate; or
- a compound of Formula (S) of the present invention can be administered in combination with an insulin-like growth factor type I (IGF-1) mimetic.
- IGF-1 insulin-like growth factor type 1
- a compound of Formula (I) of the present invention can be administered in combination with an inhaled glucocorticoid with reduced systemic side effects, including, prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, and mometasone furoate.
- a compound of Formula (I) of the present invention can be administered in combination with (a) tryptase inhibitors; (b) platelet activating factor (PAF) antagonists; (c) interleuk ⁇ n converting enzyme (ICE) inhibitors; (d) IMPDH inhibitors; (e) adhesion molecule inhibitors including VLA-4 antagonists; (f) cathepsins; (g) MAP kinase inhibitors; (h) glucose-6 phosphate dehydrogenase inhibitors; (i) kinin-Bi- and B 2 -receptor antagonists; j) anti-gout agents, e.g., colchicine; (k) xanthine oxidase inhibitors, e.g., allopurinol; (I) uricosuric agents, e.
- fibroblast growth factor e.g., basic fibroblast growth factor (bFGF);
- bFGF basic fibroblast growth factor
- GM-CSF granulocyte macrophage colony stimulating factor
- capsaicin cream e.g., capsaicin cream;
- Tachykinin NK 1 and NK 3 receptor antagonists such as NKP-608C; SB-233412 (talnetant); and D-4418; and
- elastase inhibitors such as UT-77 and ZD-0892.
- a compound of Formula (i) of the present invention can be administered in combination with an inhibitor of matrix meta ⁇ oproteases (MMPs), i.e., the stromeiysins, the collagenases, and the geiatinases, as well as aggrecanase; especially collagenase-1 (MMP-1), collagenase-2 (MMP-8), co!lagenase-3 (MMP- 13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11).
- MMPs matrix meta ⁇ oproteases
- a compound of Formula (I) of the present invention can be administered in combination with, anticancer agents such as endostatin and anglostatin or cytotoxic drugs such as adriamycin, daunomycin, cis-piatinum, etoposide, taxol, taxotere and farnesyl transferase inhibitors, VEGF inhibitors, COX-2 inhibitors and antimetabolites such as methotrexate antineoplastic agents, especially antimitotic drugs including the vinca alkaloids such as vinblastine and vincristine.
- anticancer agents such as endostatin and anglostatin or cytotoxic drugs such as adriamycin, daunomycin, cis-piatinum, etoposide, taxol, taxotere and farnesyl transferase inhibitors, VEGF inhibitors, COX-2 inhibitors and antimetabolites such as methotrexate antineoplastic agents, especially antimitotic drugs including the vinca alkaloids such
- a compound of Formula (I) of the present invention can be administered in combination with antiviral agents such as Viracept, AZT, aciclovir and famciclovir, and antisepsis compounds such as Valant.
- antiviral agents such as Viracept, AZT, aciclovir and famciclovir
- antisepsis compounds such as Valant.
- a compound of Formula (I) of the present invention can be administered in combination with cardiovascular agents such as calcium channel blockers, lipid lowering agents such as stating, fibrates, beta-blockers, ACE inhibitors, Angiotensin- 2 receptor antagonists and platelet aggregation inhibitors.
- cardiovascular agents such as calcium channel blockers, lipid lowering agents such as stating, fibrates, beta-blockers, ACE inhibitors, Angiotensin- 2 receptor antagonists and platelet aggregation inhibitors.
- a compound of Formula (I) of the present invention can be administered in combination with CNS agents such as antidepressants (such as sertraline), antiparkinsonian drugs (such as deprenyl, L-dopa, Requip, Mirapex, MAOB inhibitors such as selegine and rasagiiine, comP inhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, Nicotine agonists, Dopamine agonists and inhibitors of neuronal nitric oxide synthase), and anti-Alzheimer's drugs such as donepezil, tacrine, COX-2 inhibitors, propentofylline or metryfonate.
- CNS agents such as antidepressants (such as sertraline), antiparkinsonian drugs (such as deprenyl, L-dopa, Requip, Mirapex, MAOB inhibitors such as selegine and rasagiiine, comP inhibitors such as Tasmar, A
- a compound of Formula (I) of the present invention can be administered in combination with osteoporosis agents such as raloxifene, droloxifene, lasofoxifene or fosomax and immunosuppressant agents such as FK-506, rapamycin, cyclosporine, azathioprine, and methotrexate.
- osteoporosis agents such as raloxifene, droloxifene, lasofoxifene or fosomax
- immunosuppressant agents such as FK-506, rapamycin, cyclosporine, azathioprine, and methotrexate.
- an indole derivative X ( ⁇ . ⁇ mmol) in dry benzene (10ml) was added an acid chloride Z (e.g. 2-cyclohexylacetyl chloride, 2-cycloheptyiacetyl chloride, 2- cyclohexylpropionyl chloride, 2-cycloheptylpropionyl chloride) (13mmol) in dry benezene (1OmL) at 0 0 C.
- a solution of SnCI 4 (26.49mM) in dry benzene (15mL) was added drop-wise at O 0 C. The reaction mixture was allowed to warm to room temperature and maintained for 3 hr.
- the mixture was poured into 5% aq HCI (5OmL) and ethyl acetate (10OmL) and stirred for 10min.
- the organic layer was separated and washed with water (5OmL), sat NaHCO 3 solution (5OmL), brine (5OmL), dried over anhydrous sodium sulfate and concentrated.
- the crude material was purified by silica gel column using ethyl acetate and chloroform to obtain the pure XZ ⁇ ntOI .
- XZIntO2 (1.8mmo!) in TFA (15mL) was refiuxed for 5 hr. Then the reaction mixture concentrated to obtain a residue. This residue was dissolved in Ethyl acetate (10OmL) and washed with water (5OmL), saturated sodium bicarbonate solution (5OmL), water (5OmL) and brine (5OmL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified over silica gel column using ethyl acetate and hexane to yield XZintOS.
- the combined organic layer was once washed with brine solution and dried over anhydrous sodium sulfate and concentrated under reduced pressure,
- the crude material was purified by flash column chromatography using 100-200 mesh size silica gel and the product XZInt04 was eluted with 7% ethyl acetate/chloroform.
- Inhibition of P2X7R activity by the compounds of the present invention is assessed by measuring calcium influx in Hek293 cells (ECACC No. 85120602) which have been stably transfected with a cDNA for the human P2X7R.
- the Hek293 cells are human embryo kidney cells that do not express endogenous P2X7R (Surprenant et al. (1996) Science 272:735-738). Hek293 cells expressing P2X7R were generated by lipofectamine transfection of the human P2X7R cDNA (Genbank accession number BC011913) under the control of the human cytomegalovirus immediate-early (CMV) promoter and inserted into the pcDNA3.1 vector (Invitrogen).
- CMV cytomegalovirus immediate-early
- DMEM Dulbecco's modified eagles medium
- FEM heat- inactivated foetal calf serum (10% v/v)
- 2 mM L-glutamsne 100 units/ml penicillin, 0.1 mg/ml streptomycin, and 750 ⁇ g/ml Geneticin G418 (GibcoBRL/lnvitrogen).
- the cells were incubated in 50 ⁇ l of assay buffer containing 100 ⁇ M Fluo-4 AM fluorescent dye per well for 1 hour at room temperature.
- the assay buffer containing the Fluo-4 AM fluorescent dye was then removed, the cells were washed once with assay buffer (without Fluo-4 AM), 100 ⁇ l of assay buffer (without Fluo-4 AM) containing the test compounds was then added per well.
- IC50 half-maximal inhibitory concentration
- N-incfol-3-yi-acetamide and N-azaindof-3-yl-acetamide compounds reduce interfeukin-1 beta secretion
- IL-1 beta secretion is assessed using isolated human monocytes.
- human monocytes were purified from human blood by Ficoll-Paque from Buffy coats as follows.
- the Buffy coat is a greyish white layer of white blood cells and platelets that accumulates on the surface of sedimented erythrocytes when blood is allowed to stand or is centrifuged.
- Each Buffy coat (one per donor) was diluted with PBS and 20 ml added on top of 15 ml of Ficoll-Paque. The gradient was centrifuged at 900 g for 20 min at room temperature. The white interphase was transferred to a new tube, washed 3 times with PBS with three centrifugation steps (600, 400, 250 g), 10 min each, at room temperature.
- PBMC Peripheral Blood Mononuclear Cells
- RPMI 1640 supplemented with 5% human serum at a concentration of 1x106/ml and plated onto a 24 wells plate (5x105 cells/well).
- medium was removed and replaced with RPMI 1640 supplemented with 10% heat-inactivated fetal bovine serum to avoid IL-1 ⁇ contamination from the human serum.
- the macrophages were pre-stimulated for 2 hours with 1 ⁇ g/mL LPS at 37 0 C. Then 100 ⁇ M BzATP were added to the cells and incubated for 30 minutes at 37 0 C. AFC-5128 (see figures for concentrations) was added 5 minutes before the stimulation with BzATP. Control samples corresponded to the cells without any treatment. After incubation, the supernatants were collected by centrifugation (250 g for 5 minutes) and IL-1 ⁇ secretion was measured by using the human IL-1 beta/I L- 1 F2 Quantikine ELISA Kit following manufacturer's instructions. Several donors were tested separately for AFC-5128. Each donor was tested in triplicates for each treatment. The O. D. at 450nm was measured for each data points and the IL- 1 ⁇ concentration calculated based on a standard curve. The IL1 ⁇ concentration was further calculated to have a concentration in pg/mL/10E+6 cells, together with its standard deviation.
- This example illustrates the analgesic and anti-inflammatory benefits of the compounds of the present invention using a carrageenan-induced paw edema model of inflammation.
- Adult male Sprague Dawley rats were challenged by a subcutaneous injection of carrageenan (1% suspension, 0.1 ml), in the plantar side of the right hind paw.
- a suspension of the compound in 0.5 % methyl cellulose or a vehicle (0.5% methyl cellulose) was administered orally one hour after the carrageenan challenge.
- the paw was then marked with indelible ink at the level of the lateral malleolus so that the paw can be immersed in the Plethysmometer cell up to this mark.
- a Plethysmometer allows the measurments of small volume changes in the paw.
- An hour after compound or vehicle administration (or 2 hr of carrageenan challenge) the plantar test was performed followed by the recording of paw volume.
- each rat was place on preheated glass stand. Both of the hind paws of the animal were stimulated with a radiant heat source. The latency of paw withdrawal from the stimuli was recorded. An increase in the response latency of paw withdrawal is interpreted as an analgesic response. Three trials were given to each animal in order to obtain an average withdrawal latency. The mean Paw Withdrawal Latency (PWL) of test group was compared with the vehicle treated group.
- a compound of the present invention (the compound described in Example 2) was evaluated for increase in the paw withdrawal latency to respond to the heat stimulus which is indicative of an analgesic response.
- a compound of the present invention was also evaluated for inhibition of paw edema induced by carrageenan which is interpreted as an anti-inflammatory response.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Rheumatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Diabetes (AREA)
- Ophthalmology & Optometry (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Pulmonology (AREA)
- Dermatology (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- Oncology (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Emergency Medicine (AREA)
- Hospice & Palliative Care (AREA)
- Immunology (AREA)
- Heart & Thoracic Surgery (AREA)
- Psychology (AREA)
- Endocrinology (AREA)
- Obesity (AREA)
- Epidemiology (AREA)
Abstract
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2010237302A AU2010237302A1 (en) | 2009-04-14 | 2010-03-11 | Novel P2X7R antagonists and their use |
CA2758474A CA2758474A1 (fr) | 2009-04-14 | 2010-03-11 | Nouveaux antagonistes de p2x7r et leur utilisation |
JP2012505103A JP2012523440A (ja) | 2009-04-14 | 2010-03-11 | 新規p2x7r拮抗薬およびその使用 |
SG2011075140A SG175232A1 (en) | 2009-04-14 | 2010-03-11 | Novel p2x7r antagonists and their use |
CN2010800166929A CN102395562A (zh) | 2009-04-14 | 2010-03-11 | 新的p2x7r拮抗剂及其用途 |
MX2011010810A MX2011010810A (es) | 2009-04-14 | 2010-03-11 | Nuevos antagonistas de p2x7r y su uso. |
BRPI1014902A BRPI1014902A2 (pt) | 2009-04-14 | 2010-03-11 | composto antagonista de p2x7r, sua composição e seus usos |
EA201101479A EA201101479A1 (ru) | 2009-04-14 | 2010-03-11 | Новые p2x7r антагонисты и их применение |
IL215444A IL215444A0 (en) | 2009-04-14 | 2011-09-27 | Novel p2x7r antagonists and their use |
ZA2011/08305A ZA201108305B (en) | 2009-04-14 | 2011-11-11 | Novel p2x7r antagonists and their use |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP09005324 | 2009-04-14 | ||
EP09005324.0 | 2009-04-14 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2010118921A1 true WO2010118921A1 (fr) | 2010-10-21 |
Family
ID=42167925
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2010/053097 WO2010118921A1 (fr) | 2009-04-14 | 2010-03-11 | Nouveaux antagonistes de p2x7r et leur utilisation |
Country Status (23)
Country | Link |
---|---|
US (2) | US7919503B2 (fr) |
EP (1) | EP2243772B1 (fr) |
JP (1) | JP2012523440A (fr) |
KR (1) | KR20120006547A (fr) |
CN (1) | CN102395562A (fr) |
AT (1) | ATE541832T1 (fr) |
AU (1) | AU2010237302A1 (fr) |
BR (1) | BRPI1014902A2 (fr) |
CA (1) | CA2758474A1 (fr) |
CY (1) | CY1112758T1 (fr) |
DK (1) | DK2243772T3 (fr) |
EA (1) | EA201101479A1 (fr) |
ES (1) | ES2380908T3 (fr) |
HR (1) | HRP20120271T1 (fr) |
IL (1) | IL215444A0 (fr) |
MX (1) | MX2011010810A (fr) |
PL (1) | PL2243772T3 (fr) |
PT (1) | PT2243772E (fr) |
SG (1) | SG175232A1 (fr) |
SI (1) | SI2243772T1 (fr) |
SM (1) | SMT201200017B (fr) |
WO (1) | WO2010118921A1 (fr) |
ZA (1) | ZA201108305B (fr) |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012110190A1 (fr) | 2011-02-17 | 2012-08-23 | Affectis Pharmaceuticals Ag | Nouveaux antagonistes p2x7r et leur utilisation |
WO2012163792A1 (fr) | 2011-05-27 | 2012-12-06 | Affectis Pharmaceuticals Ag | Nouveaux antagonistes de p2x7r et leur utilisation |
WO2012163456A1 (fr) | 2011-05-27 | 2012-12-06 | Affectis Pharmaceuticals Ag | Nouveaux antagonistes de p2x7r et leur utilisation |
US9221832B2 (en) | 2011-07-22 | 2015-12-29 | Actelion Pharmaceuticals Ltd. | Heterocyclic amide derivatives as P2X7 receptor antagonists |
US9388198B2 (en) | 2013-01-22 | 2016-07-12 | Actelion Pharmaceuticals Ltd. | Heterocyclic amide derivatives as P2X7 receptor antagonists |
US9388197B2 (en) | 2013-01-22 | 2016-07-12 | Actelion Pharmaceuticals Ltd. | Heterocyclic amide derivatives as P2X7 receptor antagonists |
US9556117B2 (en) | 2012-12-18 | 2017-01-31 | Actelion Pharmaceuticals Ltd. | Indole carboxamide derivatives as P2X7 receptor antagonists |
US9718774B2 (en) | 2012-12-12 | 2017-08-01 | Idorsia Pharmaceuticals Ltd | Indole carboxamide derivatives as P2X7 receptor antagonist |
US10071167B2 (en) | 2013-05-08 | 2018-09-11 | Children's Medical Center Corporation | Method of preventing and treating type 1 diabetes, allograft rejection and lung fibrosis (by targeting the ATP/P2X7R axis) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE602009000550D1 (de) * | 2008-03-25 | 2011-02-24 | Affectis Pharmaceuticals Ag | Neuartige P2X7R-Antagonisten und ihre Verwendung |
US8815892B2 (en) | 2008-03-25 | 2014-08-26 | Affectis Pharmaceuticals Ag | P2X7R antagonists and their use |
CN102858741A (zh) * | 2010-05-14 | 2013-01-02 | 阿费克蒂斯制药股份公司 | 制备p2x7r拮抗剂的新方法 |
WO2012149285A1 (fr) * | 2011-04-28 | 2012-11-01 | Claire Mitchell | Méthode de traitement d'une dégénérescence maculaire par la modulation des récepteurs p2y12 ou p2x7 |
WO2013082565A1 (fr) * | 2011-12-02 | 2013-06-06 | Michael Kaleko | Thérapies pour des troubles de la cornée et de la conjonctive |
CN104066737B (zh) * | 2012-01-20 | 2016-06-08 | 埃科特莱茵药品有限公司 | 作为p2x7受体拮抗剂的杂环酰胺衍生物 |
WO2020150417A2 (fr) * | 2019-01-17 | 2020-07-23 | Ifm Due, Inc. | Composés et compositions pour traiter des états pathologiques associés à une activité de sting |
Citations (76)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998038179A1 (fr) | 1997-02-26 | 1998-09-03 | Glaxo Group Limited | Derives d'hydroxamate utilises comme inhibiteurs de metalloprotease |
WO1999018074A1 (fr) | 1997-10-03 | 1999-04-15 | Britol-Myers Squibb Pharma Company | Inhibiteurs de metalloprotease a base de lactame |
WO1999029660A1 (fr) | 1997-12-05 | 1999-06-17 | Astrazeneca Uk Limited | Derives d'adamantane |
WO1999029686A1 (fr) | 1997-12-05 | 1999-06-17 | Astrazeneca Uk Limited | Nouveaux composes |
WO1999029661A1 (fr) | 1997-12-05 | 1999-06-17 | Astrazeneca Uk Limited | Derives d'adamantane |
WO1999065867A1 (fr) | 1998-06-17 | 1999-12-23 | Du Pont Pharmaceuticals Company | Acides hydroxamiques cycliques utilises en tant qu'inhibiteurs de metalloproteases |
WO2000000465A1 (fr) | 1998-06-26 | 2000-01-06 | F. Hoffmann-La Roche Ag | Derives d'hydrazine |
WO2000009485A1 (fr) | 1998-08-12 | 2000-02-24 | Pfizer Products Inc. | Derives d'acide hydroxamique de pipecolate hydroxy |
WO2000061569A1 (fr) | 1999-04-09 | 2000-10-19 | Astrazeneca Ab | Derives d'adamantane |
WO2000071529A1 (fr) | 1999-05-25 | 2000-11-30 | Astrazeneca Ab | Composes phenyle substitues a activite immunosuppresseur et compositions pharmaceutiques |
US6225311B1 (en) | 1999-01-27 | 2001-05-01 | American Cyanamid Company | Acetylenic α-amino acid-based sulfonamide hydroxamic acid tace inhibitors |
WO2001042194A1 (fr) | 1999-12-09 | 2001-06-14 | Astrazeneca Ab | Derives d'adamantane |
WO2001044170A1 (fr) | 1999-12-17 | 2001-06-21 | Astrazeneca Ab | Derives d'adamantane |
WO2001044213A1 (fr) | 1999-12-17 | 2001-06-21 | Astrazeneca Ab | Nouveaux antagonistes des recepteurs p2x7 utiles dans le traitement de maladies inflammatoires, immunitaires ou cardiovasculaires |
WO2001046200A1 (fr) | 1999-12-22 | 2001-06-28 | Astrazeneca Ab | Nouveaux derives de piperidine et de piperazine |
WO2001094338A1 (fr) | 2000-06-07 | 2001-12-13 | Astrazeneca Ab | Derives d'admantane |
WO2002018326A1 (fr) | 2000-08-31 | 2002-03-07 | Wakunaga Pharmaceutical Co., Ltd. | Nouveaux derives d'acide propenohydroxamique |
WO2002096426A1 (fr) | 2001-05-25 | 2002-12-05 | Bristol-Myers Squibb Company | Derives d'hydantoine utilises comme inhibiteurs des metalloproteinases matricielles |
WO2003016248A2 (fr) | 2001-08-17 | 2003-02-27 | Bristol-Myers Squibb Company Patent Department | Hydroxamates bicycliques utilises comme inhibiteurs de metalloproteinases matricielles et/ou enzyme de conversion du tnf-$g(a) (tace) |
WO2003024899A2 (fr) | 2001-09-17 | 2003-03-27 | Bristol-Myers Squibb Company | Acides hydroxamiques cycliques utilises comme inhibiteurs de metalloproteinases matricielles et/ou d'enzyme de conversion du tnf-$g(a) (tace) |
WO2003031431A1 (fr) | 2001-10-09 | 2003-04-17 | Bristol-Myers Squibb Company | Derives de sulfone cycliques utilises comme inhibiteurs de metalloproteinases matricielles et/ou d'enzyme de conversion du tnf-$g(a) (tace) |
WO2003040103A1 (fr) | 2001-11-02 | 2003-05-15 | Bristol-Myers Squibb Company | Derives $g(b)-sulfone utilises comme inhibiteurs de metalloproteinases matricielles et/ou enzyme de conversion de tnf-$g(a) (tace) |
WO2003041707A1 (fr) | 2001-11-16 | 2003-05-22 | Astrazeneca Ab | Derives de n-adamantylmethyle et intermediaires utilises dans des compositions pharmaceutiques et leurs procedes de preparation |
WO2003042191A1 (fr) | 2001-11-12 | 2003-05-22 | Pfizer Products Inc. | Benzamide et heteroarylamide utilises comme antagonistes du recepteur p2x7 |
WO2003042190A1 (fr) | 2001-11-12 | 2003-05-22 | Pfizer Products Inc. | Derives de n-adamantylalkyle benzamide en tant qu'antagonistes du recepteur p2x7 |
WO2003047515A2 (fr) | 2001-11-30 | 2003-06-12 | The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Antagonistes du recepteur p2x7 |
WO2003053941A2 (fr) | 2001-12-20 | 2003-07-03 | Bristol-Myers Squibb Company | Derives de l'acide barbiturique utilises comme inhibiteurs de l'enzyme de conversion du tnf-alpha (tace) et/ou de metalloproteases matricielles |
WO2003055856A2 (fr) | 2001-10-17 | 2003-07-10 | Bristol-Myers Squibb Company | Derives bicycliques de lactame utilises en tant qu'inhibiteurs de metalloproteases matricielles et/ou d'enzyme de conversion du tnf-alpha (tace) |
WO2003059353A1 (fr) | 2001-12-21 | 2003-07-24 | King Pharmaceuticals Research And Development, Inc. | Derives de tyrosyle et leur utilisation comme modulateurs du recepteur p2x7 |
WO2003080579A1 (fr) | 2002-03-25 | 2003-10-02 | Astrazeneca Ab | Nouveaux derives d'adamantane |
WO2003079986A2 (fr) | 2002-03-18 | 2003-10-02 | Bristol-Myers Squibb Company | Derives d'uracile utilises en tant qu'inhibiteurs de l'enzyme tnf-alpha convertase (tace) et metalloproteases matricielles |
WO2004006925A1 (fr) | 2002-07-13 | 2004-01-22 | Astrazeneca Ab | N-sulfonylpiperidines utilises comme inhibiteurs de metalloproteinase (tace) (enzyme de conversion du facteur de necrose tumorale $g(a)) |
WO2004012663A2 (fr) | 2002-08-01 | 2004-02-12 | Bristol-Myers Squibb Company | Derives d'yhydantoine utilises comme inhibiteurs de metalloproteases maticielles et/ou d'enzyme de conversion de tnf-alpha |
WO2004032846A2 (fr) | 2002-10-07 | 2004-04-22 | Bristol-Myers Squibb Company | Derives de la triazolone et de la triazolethione, inhibiteurs des metalloproteinases de matrices et/ou de l'enzyme de conversion du tnf$g(a) |
WO2004033632A2 (fr) | 2002-10-04 | 2004-04-22 | Bristol-Myers Squibb Company | Derives d'hydantoine en tant qu'inhibiteurs de metalloproteinases matricielles et/ou de l'enzyme de conversion de tnf-alpha (tace) |
WO2004043349A2 (fr) | 2002-11-06 | 2004-05-27 | Bristol-Myers Squibb Company | Derives d'isoxazoline comme inhibiteurs de metalloproteases matricielles et/ou d'enzyme de conversion de tnf-$g(a) |
WO2004058731A1 (fr) | 2002-12-31 | 2004-07-15 | Pfizer Products Inc. | Inhibiteurs benzamidiques du recepteur p2x7 |
WO2004058270A1 (fr) | 2002-12-31 | 2004-07-15 | Pfizer Products Inc. | Derives de 3-(3,5-dioxo-4,5-dihydro-3h-(1,2,4)triazin-2-yl)-benzamide utilises comme inhibiteurs de p2x7 pour le traitement de maladies inflammatoires |
WO2004074224A1 (fr) | 2003-02-21 | 2004-09-02 | Astrazeneca Ab | Derives d'adamantane, procedes pour les preparer et compositions pharmaceutiques les contenant |
WO2004096206A2 (fr) | 2003-04-25 | 2004-11-11 | Pharmacia Corporation | Combinaison therapeutique d'un inhibiteur de cox-2 et d'un inhibiteur de tace |
WO2004099146A1 (fr) | 2003-05-12 | 2004-11-18 | Pfizer Products Inc. | Inhibiteurs benzamidiques du recepteur p2x7 |
WO2004106305A1 (fr) | 2003-06-02 | 2004-12-09 | Astrazeneca Ab | Nouveaux comoses |
WO2004108086A2 (fr) | 2003-06-05 | 2004-12-16 | Bristol-Myers Squibb Company | Derives d'hydantoine en tant qu'inhibiteurs de l'enzyme de conversion du facteur ?lpha de necrose tumorale (tace) |
WO2005009968A1 (fr) | 2003-07-28 | 2005-02-03 | Astrazeneca Ab | Derives de la quinoline et leur utilisation en therapie |
WO2005014555A1 (fr) | 2003-07-21 | 2005-02-17 | Aventis Pharmaceuticals Inc. | 4,5-dihydro-imidazole utilise comme antagonistes des canaux ioniques p2x7 |
WO2005014529A1 (fr) | 2003-08-08 | 2005-02-17 | Astrazeneca Ab | Derives de 2-adamantyle en tant qu'antagonistes du recepteur p2x7 |
WO2005019182A1 (fr) | 2003-08-20 | 2005-03-03 | Bayer Healthcare Ag | Derives de pyrazolylmethylbenzamide utilises comme antagonistes du recepteur p2xt |
WO2005039590A1 (fr) | 2003-10-21 | 2005-05-06 | Inspire Pharmaceuticals, Inc. | Compositions non-nucleotidiques et procede de traitement de la douleur |
WO2005111003A1 (fr) | 2004-04-29 | 2005-11-24 | Abbott Laboratories | Analogues d’amino-tétrazoles et méthodes d’utilisation |
WO2006003513A1 (fr) | 2004-06-29 | 2006-01-12 | Pfizer Products Inc. | Procede de preparation de derives de 5-`4-(2-hydroxy-ethyl)-3,5-dioxo-4,5-dihydro-3h-`1,2,4-triazin-2-yl-benzamide aant une activite inhibant p2x7 par reaction du derive non substitue en position 4 de triazine avec un oxyrane en presence d'un acide de lewis |
WO2006003500A1 (fr) | 2004-06-29 | 2006-01-12 | Pfizer Products Inc. | Procedes permettant de preparer des derives de 5-[4-(2-hydroxy-propyl)-3,5-dioxo-4,5-dihydro-3h-[1,2,4]triazin-2-yl]-benzamides par deprotection des precurseurs proteges par hydroxyle |
WO2006017406A1 (fr) | 2004-08-02 | 2006-02-16 | Abbott Laboratories | Cyanoamidines antagonistes de p2x7 pour le traitement de la douleur |
WO2006025783A1 (fr) | 2004-08-30 | 2006-03-09 | Astrazeneca Ab | Derives d'adamantyl utilises comme antagonistes du recepteur p2x7 |
WO2006059945A1 (fr) | 2004-11-30 | 2006-06-08 | Astrazeneca Ab | Nouveaux composes |
WO2006067444A1 (fr) | 2004-12-24 | 2006-06-29 | Astrazeneca Ab | Dérivés d'amide |
WO2006080884A1 (fr) | 2005-01-27 | 2006-08-03 | Astrazeneca Ab | Nouveaux composes biaromatiques, inhibiteurs du recepteur p2x7 |
WO2006086229A1 (fr) | 2005-02-08 | 2006-08-17 | Abbott Laboratories | Utilisation d'antagonistes selectifs du recepteur p2x7 |
WO2006102610A2 (fr) | 2005-03-24 | 2006-09-28 | Renovis, Inc. | Composes bicycloheteroaryle utilises en tant que modulateurs de p2x7 et leurs utilisations |
WO2006110516A1 (fr) | 2005-04-11 | 2006-10-19 | Abbott Laboratories | Antagonistes de l'acylhydrazide p2x7 et leurs utilisations |
WO2006136004A1 (fr) | 2005-05-05 | 2006-12-28 | Medicure International Inc. | Inhibition des voies dependantes de p2x7 mediees par l'atp au moyen de pyridoxal-5-phosphate et de composes associes a la vitamine b6 |
WO2007016597A2 (fr) | 2005-07-29 | 2007-02-08 | The Regents Of The University Of California | Ciblage de secretion de facteur de croissance dependant d'enzyme de conversion de tnf-alpha (tace) dans une therapie anticancereuse |
WO2007025366A1 (fr) | 2005-08-29 | 2007-03-08 | Irma Bernatchez-Lemaire | Utilisation de composes histogranine et du type histogranine comme inhibiteurs de la fonction du recepteur p2x7 et comme agents anti-arthritiques |
WO2007028022A2 (fr) | 2005-09-01 | 2007-03-08 | Renovis, Inc. | Nouveaux composes servant de modulateurs de p2x7 et leurs utilisations |
WO2007056091A2 (fr) | 2005-11-09 | 2007-05-18 | Abbott Laboratories | Antagonistes des recepteurs p2x7 et utilisations associees |
WO2007056046A1 (fr) | 2005-11-07 | 2007-05-18 | Abbott Laboratories | Antagonistes des recepteurs p2x7 et methodes d'utilisation |
WO2007109182A2 (fr) | 2006-03-16 | 2007-09-27 | Renovis, Inc. | Composés de bicyclohétéroaryle en tant que modulateurs de p2x7 et leurs utilisations |
WO2007109192A2 (fr) | 2006-03-16 | 2007-09-27 | Renovis, Inc. | Composés de bicyclohétéroaryle en tant que modulateurs de p2x7 et leurs utilisations |
WO2007109160A2 (fr) | 2006-03-16 | 2007-09-27 | Renovis, Inc. | Composés de bicyclohétéroaryle en tant que modulateurs de p2x7 et leurs utilisations |
WO2007109154A2 (fr) | 2006-03-16 | 2007-09-27 | Renovis, Inc. | Composés de bicyclohétéroaryle en tant que modulateurs de p2x7 modulators et leurs utilisations |
WO2007109172A2 (fr) | 2006-03-16 | 2007-09-27 | Renovis, Inc. | Composés de bicyclohétéroaryle en tant que modulateurs de p2x7 et leurs utilisations |
WO2007109201A2 (fr) | 2006-03-16 | 2007-09-27 | Renovis, Inc. | Composés de bicyclohétéroaryle en tant que modulateur de p2x7 et leurs utilisations |
WO2007141267A1 (fr) | 2006-06-06 | 2007-12-13 | Glaxo Group Limited | Dérivés de n- (phénylméthyl) -2- (1h-pyraz0l-4-yl) acétamide utilisés comme antagonistes fp2x7 pour le traitement de la douleur, de l'inflammation et de la neurodégénérescence |
WO2007141269A1 (fr) | 2006-06-06 | 2007-12-13 | Glaxo Group Limited | Nouveaux antagonistes de récepteurs et leurs procédés d'utilisation |
WO2008003697A1 (fr) | 2006-07-06 | 2008-01-10 | Glaxo Group Limited | N-phenylmethyl -5-oxo-proline-2-amides substitués tenant lieu d'antagonistes du récepteur p2x7 et procédés d'utilisation |
WO2008005368A2 (fr) | 2006-06-30 | 2008-01-10 | Abbott Laboratories | Pipérazines en tant qu'antagonistes de p2x7 |
WO2009023623A1 (fr) * | 2007-08-10 | 2009-02-19 | H, Lundbeck A/S | Analogues d'hétéroarylamides |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3705175A (en) * | 1969-04-01 | 1972-12-05 | Egyt Gyogyszervegyeszeti Gyar | Indazole-3-carboxylic amides |
ITMI20030287A1 (it) * | 2003-02-18 | 2004-08-19 | Acraf | Indazolammidi dotate di attivita' analgesica metodo, per |
WO2005005415A1 (fr) * | 2003-07-09 | 2005-01-20 | Biolipox Ab | Indoles utilises dans le traitement de l'inflammation |
SE0302035D0 (sv) * | 2003-07-09 | 2003-07-09 | Biolipox Ab | New compound |
DE602009000550D1 (de) * | 2008-03-25 | 2011-02-24 | Affectis Pharmaceuticals Ag | Neuartige P2X7R-Antagonisten und ihre Verwendung |
-
2010
- 2010-03-11 AU AU2010237302A patent/AU2010237302A1/en not_active Abandoned
- 2010-03-11 SG SG2011075140A patent/SG175232A1/en unknown
- 2010-03-11 MX MX2011010810A patent/MX2011010810A/es active IP Right Grant
- 2010-03-11 EA EA201101479A patent/EA201101479A1/ru unknown
- 2010-03-11 AT AT10156190T patent/ATE541832T1/de active
- 2010-03-11 PT PT10156190T patent/PT2243772E/pt unknown
- 2010-03-11 PL PL10156190T patent/PL2243772T3/pl unknown
- 2010-03-11 WO PCT/EP2010/053097 patent/WO2010118921A1/fr active Application Filing
- 2010-03-11 KR KR1020117026988A patent/KR20120006547A/ko not_active Application Discontinuation
- 2010-03-11 CA CA2758474A patent/CA2758474A1/fr not_active Abandoned
- 2010-03-11 JP JP2012505103A patent/JP2012523440A/ja active Pending
- 2010-03-11 ES ES10156190T patent/ES2380908T3/es active Active
- 2010-03-11 DK DK10156190.0T patent/DK2243772T3/da active
- 2010-03-11 CN CN2010800166929A patent/CN102395562A/zh active Pending
- 2010-03-11 EP EP10156190A patent/EP2243772B1/fr not_active Not-in-force
- 2010-03-11 BR BRPI1014902A patent/BRPI1014902A2/pt not_active IP Right Cessation
- 2010-03-11 SI SI201030020T patent/SI2243772T1/sl unknown
- 2010-04-12 US US12/758,557 patent/US7919503B2/en not_active Expired - Fee Related
-
2011
- 2011-02-25 US US13/035,614 patent/US8268861B2/en not_active Expired - Fee Related
- 2011-09-27 IL IL215444A patent/IL215444A0/en unknown
- 2011-11-11 ZA ZA2011/08305A patent/ZA201108305B/en unknown
-
2012
- 2012-03-27 HR HR20120271T patent/HRP20120271T1/hr unknown
- 2012-04-04 CY CY20121100340T patent/CY1112758T1/el unknown
- 2012-04-25 SM SM201200017T patent/SMT201200017B/it unknown
Patent Citations (77)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998038179A1 (fr) | 1997-02-26 | 1998-09-03 | Glaxo Group Limited | Derives d'hydroxamate utilises comme inhibiteurs de metalloprotease |
WO1999018074A1 (fr) | 1997-10-03 | 1999-04-15 | Britol-Myers Squibb Pharma Company | Inhibiteurs de metalloprotease a base de lactame |
WO1999029660A1 (fr) | 1997-12-05 | 1999-06-17 | Astrazeneca Uk Limited | Derives d'adamantane |
WO1999029686A1 (fr) | 1997-12-05 | 1999-06-17 | Astrazeneca Uk Limited | Nouveaux composes |
WO1999029661A1 (fr) | 1997-12-05 | 1999-06-17 | Astrazeneca Uk Limited | Derives d'adamantane |
WO1999065867A1 (fr) | 1998-06-17 | 1999-12-23 | Du Pont Pharmaceuticals Company | Acides hydroxamiques cycliques utilises en tant qu'inhibiteurs de metalloproteases |
WO2000000465A1 (fr) | 1998-06-26 | 2000-01-06 | F. Hoffmann-La Roche Ag | Derives d'hydrazine |
WO2000009485A1 (fr) | 1998-08-12 | 2000-02-24 | Pfizer Products Inc. | Derives d'acide hydroxamique de pipecolate hydroxy |
US6225311B1 (en) | 1999-01-27 | 2001-05-01 | American Cyanamid Company | Acetylenic α-amino acid-based sulfonamide hydroxamic acid tace inhibitors |
WO2000061569A1 (fr) | 1999-04-09 | 2000-10-19 | Astrazeneca Ab | Derives d'adamantane |
WO2000071529A1 (fr) | 1999-05-25 | 2000-11-30 | Astrazeneca Ab | Composes phenyle substitues a activite immunosuppresseur et compositions pharmaceutiques |
WO2001042194A1 (fr) | 1999-12-09 | 2001-06-14 | Astrazeneca Ab | Derives d'adamantane |
WO2001044170A1 (fr) | 1999-12-17 | 2001-06-21 | Astrazeneca Ab | Derives d'adamantane |
WO2001044213A1 (fr) | 1999-12-17 | 2001-06-21 | Astrazeneca Ab | Nouveaux antagonistes des recepteurs p2x7 utiles dans le traitement de maladies inflammatoires, immunitaires ou cardiovasculaires |
WO2001046200A1 (fr) | 1999-12-22 | 2001-06-28 | Astrazeneca Ab | Nouveaux derives de piperidine et de piperazine |
WO2001094338A1 (fr) | 2000-06-07 | 2001-12-13 | Astrazeneca Ab | Derives d'admantane |
WO2002018326A1 (fr) | 2000-08-31 | 2002-03-07 | Wakunaga Pharmaceutical Co., Ltd. | Nouveaux derives d'acide propenohydroxamique |
WO2002096426A1 (fr) | 2001-05-25 | 2002-12-05 | Bristol-Myers Squibb Company | Derives d'hydantoine utilises comme inhibiteurs des metalloproteinases matricielles |
WO2003016248A2 (fr) | 2001-08-17 | 2003-02-27 | Bristol-Myers Squibb Company Patent Department | Hydroxamates bicycliques utilises comme inhibiteurs de metalloproteinases matricielles et/ou enzyme de conversion du tnf-$g(a) (tace) |
WO2003024899A2 (fr) | 2001-09-17 | 2003-03-27 | Bristol-Myers Squibb Company | Acides hydroxamiques cycliques utilises comme inhibiteurs de metalloproteinases matricielles et/ou d'enzyme de conversion du tnf-$g(a) (tace) |
WO2003031431A1 (fr) | 2001-10-09 | 2003-04-17 | Bristol-Myers Squibb Company | Derives de sulfone cycliques utilises comme inhibiteurs de metalloproteinases matricielles et/ou d'enzyme de conversion du tnf-$g(a) (tace) |
WO2003055856A2 (fr) | 2001-10-17 | 2003-07-10 | Bristol-Myers Squibb Company | Derives bicycliques de lactame utilises en tant qu'inhibiteurs de metalloproteases matricielles et/ou d'enzyme de conversion du tnf-alpha (tace) |
WO2003040103A1 (fr) | 2001-11-02 | 2003-05-15 | Bristol-Myers Squibb Company | Derives $g(b)-sulfone utilises comme inhibiteurs de metalloproteinases matricielles et/ou enzyme de conversion de tnf-$g(a) (tace) |
WO2003042191A1 (fr) | 2001-11-12 | 2003-05-22 | Pfizer Products Inc. | Benzamide et heteroarylamide utilises comme antagonistes du recepteur p2x7 |
WO2003042190A1 (fr) | 2001-11-12 | 2003-05-22 | Pfizer Products Inc. | Derives de n-adamantylalkyle benzamide en tant qu'antagonistes du recepteur p2x7 |
WO2003041707A1 (fr) | 2001-11-16 | 2003-05-22 | Astrazeneca Ab | Derives de n-adamantylmethyle et intermediaires utilises dans des compositions pharmaceutiques et leurs procedes de preparation |
WO2003047515A2 (fr) | 2001-11-30 | 2003-06-12 | The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Antagonistes du recepteur p2x7 |
WO2003053941A2 (fr) | 2001-12-20 | 2003-07-03 | Bristol-Myers Squibb Company | Derives de l'acide barbiturique utilises comme inhibiteurs de l'enzyme de conversion du tnf-alpha (tace) et/ou de metalloproteases matricielles |
WO2003059353A1 (fr) | 2001-12-21 | 2003-07-24 | King Pharmaceuticals Research And Development, Inc. | Derives de tyrosyle et leur utilisation comme modulateurs du recepteur p2x7 |
WO2003079986A2 (fr) | 2002-03-18 | 2003-10-02 | Bristol-Myers Squibb Company | Derives d'uracile utilises en tant qu'inhibiteurs de l'enzyme tnf-alpha convertase (tace) et metalloproteases matricielles |
WO2003080579A1 (fr) | 2002-03-25 | 2003-10-02 | Astrazeneca Ab | Nouveaux derives d'adamantane |
WO2004006925A1 (fr) | 2002-07-13 | 2004-01-22 | Astrazeneca Ab | N-sulfonylpiperidines utilises comme inhibiteurs de metalloproteinase (tace) (enzyme de conversion du facteur de necrose tumorale $g(a)) |
WO2004012663A2 (fr) | 2002-08-01 | 2004-02-12 | Bristol-Myers Squibb Company | Derives d'yhydantoine utilises comme inhibiteurs de metalloproteases maticielles et/ou d'enzyme de conversion de tnf-alpha |
WO2004033632A2 (fr) | 2002-10-04 | 2004-04-22 | Bristol-Myers Squibb Company | Derives d'hydantoine en tant qu'inhibiteurs de metalloproteinases matricielles et/ou de l'enzyme de conversion de tnf-alpha (tace) |
WO2004032846A2 (fr) | 2002-10-07 | 2004-04-22 | Bristol-Myers Squibb Company | Derives de la triazolone et de la triazolethione, inhibiteurs des metalloproteinases de matrices et/ou de l'enzyme de conversion du tnf$g(a) |
WO2004043349A2 (fr) | 2002-11-06 | 2004-05-27 | Bristol-Myers Squibb Company | Derives d'isoxazoline comme inhibiteurs de metalloproteases matricielles et/ou d'enzyme de conversion de tnf-$g(a) |
WO2004058731A1 (fr) | 2002-12-31 | 2004-07-15 | Pfizer Products Inc. | Inhibiteurs benzamidiques du recepteur p2x7 |
WO2004058270A1 (fr) | 2002-12-31 | 2004-07-15 | Pfizer Products Inc. | Derives de 3-(3,5-dioxo-4,5-dihydro-3h-(1,2,4)triazin-2-yl)-benzamide utilises comme inhibiteurs de p2x7 pour le traitement de maladies inflammatoires |
WO2004074224A1 (fr) | 2003-02-21 | 2004-09-02 | Astrazeneca Ab | Derives d'adamantane, procedes pour les preparer et compositions pharmaceutiques les contenant |
WO2004096206A2 (fr) | 2003-04-25 | 2004-11-11 | Pharmacia Corporation | Combinaison therapeutique d'un inhibiteur de cox-2 et d'un inhibiteur de tace |
WO2004099146A1 (fr) | 2003-05-12 | 2004-11-18 | Pfizer Products Inc. | Inhibiteurs benzamidiques du recepteur p2x7 |
WO2004106305A1 (fr) | 2003-06-02 | 2004-12-09 | Astrazeneca Ab | Nouveaux comoses |
WO2004108086A2 (fr) | 2003-06-05 | 2004-12-16 | Bristol-Myers Squibb Company | Derives d'hydantoine en tant qu'inhibiteurs de l'enzyme de conversion du facteur ?lpha de necrose tumorale (tace) |
WO2005014555A1 (fr) | 2003-07-21 | 2005-02-17 | Aventis Pharmaceuticals Inc. | 4,5-dihydro-imidazole utilise comme antagonistes des canaux ioniques p2x7 |
WO2005009968A1 (fr) | 2003-07-28 | 2005-02-03 | Astrazeneca Ab | Derives de la quinoline et leur utilisation en therapie |
WO2005014529A1 (fr) | 2003-08-08 | 2005-02-17 | Astrazeneca Ab | Derives de 2-adamantyle en tant qu'antagonistes du recepteur p2x7 |
WO2005019182A1 (fr) | 2003-08-20 | 2005-03-03 | Bayer Healthcare Ag | Derives de pyrazolylmethylbenzamide utilises comme antagonistes du recepteur p2xt |
WO2005039590A1 (fr) | 2003-10-21 | 2005-05-06 | Inspire Pharmaceuticals, Inc. | Compositions non-nucleotidiques et procede de traitement de la douleur |
WO2005111003A1 (fr) | 2004-04-29 | 2005-11-24 | Abbott Laboratories | Analogues d’amino-tétrazoles et méthodes d’utilisation |
WO2006003513A1 (fr) | 2004-06-29 | 2006-01-12 | Pfizer Products Inc. | Procede de preparation de derives de 5-`4-(2-hydroxy-ethyl)-3,5-dioxo-4,5-dihydro-3h-`1,2,4-triazin-2-yl-benzamide aant une activite inhibant p2x7 par reaction du derive non substitue en position 4 de triazine avec un oxyrane en presence d'un acide de lewis |
WO2006003500A1 (fr) | 2004-06-29 | 2006-01-12 | Pfizer Products Inc. | Procedes permettant de preparer des derives de 5-[4-(2-hydroxy-propyl)-3,5-dioxo-4,5-dihydro-3h-[1,2,4]triazin-2-yl]-benzamides par deprotection des precurseurs proteges par hydroxyle |
WO2006017406A1 (fr) | 2004-08-02 | 2006-02-16 | Abbott Laboratories | Cyanoamidines antagonistes de p2x7 pour le traitement de la douleur |
WO2006025783A1 (fr) | 2004-08-30 | 2006-03-09 | Astrazeneca Ab | Derives d'adamantyl utilises comme antagonistes du recepteur p2x7 |
WO2006059945A1 (fr) | 2004-11-30 | 2006-06-08 | Astrazeneca Ab | Nouveaux composes |
WO2006067444A1 (fr) | 2004-12-24 | 2006-06-29 | Astrazeneca Ab | Dérivés d'amide |
WO2006080884A1 (fr) | 2005-01-27 | 2006-08-03 | Astrazeneca Ab | Nouveaux composes biaromatiques, inhibiteurs du recepteur p2x7 |
WO2006086229A1 (fr) | 2005-02-08 | 2006-08-17 | Abbott Laboratories | Utilisation d'antagonistes selectifs du recepteur p2x7 |
WO2006102610A2 (fr) | 2005-03-24 | 2006-09-28 | Renovis, Inc. | Composes bicycloheteroaryle utilises en tant que modulateurs de p2x7 et leurs utilisations |
WO2006102588A1 (fr) | 2005-03-24 | 2006-09-28 | Renovis, Inc. | Composes bicycloheteroaryle servant de modulateurs de p2x7 et utilisations de ceux-ci |
WO2006110516A1 (fr) | 2005-04-11 | 2006-10-19 | Abbott Laboratories | Antagonistes de l'acylhydrazide p2x7 et leurs utilisations |
WO2006136004A1 (fr) | 2005-05-05 | 2006-12-28 | Medicure International Inc. | Inhibition des voies dependantes de p2x7 mediees par l'atp au moyen de pyridoxal-5-phosphate et de composes associes a la vitamine b6 |
WO2007016597A2 (fr) | 2005-07-29 | 2007-02-08 | The Regents Of The University Of California | Ciblage de secretion de facteur de croissance dependant d'enzyme de conversion de tnf-alpha (tace) dans une therapie anticancereuse |
WO2007025366A1 (fr) | 2005-08-29 | 2007-03-08 | Irma Bernatchez-Lemaire | Utilisation de composes histogranine et du type histogranine comme inhibiteurs de la fonction du recepteur p2x7 et comme agents anti-arthritiques |
WO2007028022A2 (fr) | 2005-09-01 | 2007-03-08 | Renovis, Inc. | Nouveaux composes servant de modulateurs de p2x7 et leurs utilisations |
WO2007056046A1 (fr) | 2005-11-07 | 2007-05-18 | Abbott Laboratories | Antagonistes des recepteurs p2x7 et methodes d'utilisation |
WO2007056091A2 (fr) | 2005-11-09 | 2007-05-18 | Abbott Laboratories | Antagonistes des recepteurs p2x7 et utilisations associees |
WO2007109182A2 (fr) | 2006-03-16 | 2007-09-27 | Renovis, Inc. | Composés de bicyclohétéroaryle en tant que modulateurs de p2x7 et leurs utilisations |
WO2007109192A2 (fr) | 2006-03-16 | 2007-09-27 | Renovis, Inc. | Composés de bicyclohétéroaryle en tant que modulateurs de p2x7 et leurs utilisations |
WO2007109160A2 (fr) | 2006-03-16 | 2007-09-27 | Renovis, Inc. | Composés de bicyclohétéroaryle en tant que modulateurs de p2x7 et leurs utilisations |
WO2007109154A2 (fr) | 2006-03-16 | 2007-09-27 | Renovis, Inc. | Composés de bicyclohétéroaryle en tant que modulateurs de p2x7 modulators et leurs utilisations |
WO2007109172A2 (fr) | 2006-03-16 | 2007-09-27 | Renovis, Inc. | Composés de bicyclohétéroaryle en tant que modulateurs de p2x7 et leurs utilisations |
WO2007109201A2 (fr) | 2006-03-16 | 2007-09-27 | Renovis, Inc. | Composés de bicyclohétéroaryle en tant que modulateur de p2x7 et leurs utilisations |
WO2007141267A1 (fr) | 2006-06-06 | 2007-12-13 | Glaxo Group Limited | Dérivés de n- (phénylméthyl) -2- (1h-pyraz0l-4-yl) acétamide utilisés comme antagonistes fp2x7 pour le traitement de la douleur, de l'inflammation et de la neurodégénérescence |
WO2007141269A1 (fr) | 2006-06-06 | 2007-12-13 | Glaxo Group Limited | Nouveaux antagonistes de récepteurs et leurs procédés d'utilisation |
WO2008005368A2 (fr) | 2006-06-30 | 2008-01-10 | Abbott Laboratories | Pipérazines en tant qu'antagonistes de p2x7 |
WO2008003697A1 (fr) | 2006-07-06 | 2008-01-10 | Glaxo Group Limited | N-phenylmethyl -5-oxo-proline-2-amides substitués tenant lieu d'antagonistes du récepteur p2x7 et procédés d'utilisation |
WO2009023623A1 (fr) * | 2007-08-10 | 2009-02-19 | H, Lundbeck A/S | Analogues d'hétéroarylamides |
Non-Patent Citations (30)
Title |
---|
ANDERSON; NEDERGAARD, TRENDS NEUROSCIEN, vol. 29, 2006, pages 257 - 262 |
ANSEL ET AL.: "Pharmaceutical Dosage Forms and Drug Delivery Systems", 1999, LIPPINCOTT WILLIAMS & WILKINS PUBLISHERS |
BARICORDI ET AL., BLOOD, vol. 87, 1996, pages 682 - 690 |
CHEN ET AL., J. BIOL. CHEM., vol. 268, 1993, pages 8199 - 8203 |
CHESSELL ET AL., PAIN, vol. 114, 2005, pages 386 - 396 |
COLLO ET AL., NEUROPHARMACOL, vol. 36, 1997, pages 1277 - 1283 |
COLLO ET AL., NEUROPHARMACOLOGY, vol. 36, 1997, pages 1277 - 1283 |
DAHLQVIST; DIAMANT, ACTA PHYSIOL. SCAND., vol. 34, 1974, pages 368 - 384 |
DI VIRGILIO ET AL., CELL, vol. 5, 1998, pages 191 - 199 |
FALZONI ET AL., J. CLIN. INVEST., vol. 95, 1995, pages 1207 - 1216 |
FERRARI ET AL., J IMMUNOL, vol. 176, 2006, pages 3877 - 3883 |
FERRARI ET AL., J. LMMUNOL, vol. 156, 1996, pages 1531 - 1539 |
GORDON, BIOCHEM. J., vol. 233, 1986, pages 309 - 319 |
GREENBERG, J. BIOL. CHEM., vol. 263, 1988, pages 10337 - 10343 |
GRIFFITHS ET AL., J. LMMOL., vol. 154, 1995, pages 2821 - 2828 |
HUMPHREYS ET AL., MOL. PHARMACOL., vol. 54, 1998, pages 22 - 32 |
JIANG ET AL., MOL. PHAMACOL., vol. 58, 2000, pages 82 - 88 |
NARCISSE, GLIA, vol. 49, 2005, pages 245 - 258 |
NORTH; SURPRENANT, ANNUAL REV. PHARMACOLOGY TOXICOLOGY, vol. 40, 2000, pages 563 - 580 |
PARVATHENANI ET AL., J BIOL CHEM, vol. 278, 2003, pages 13300 - 13317 |
PERREGAUX; GABEL, J BIOL CHEM, vol. 269, 1998, pages 15195 - 15203 |
RASSENDREN ET AL., J. BIOL. CHEM., vol. 272, 1997, pages 5482 - 5486 |
ROMAGNOLI R ET AL: "Recent progress in the discovery of antagonists acting at P2X7 receptor", EXPERT OPINION ON THERAPEUTIC PATENTS, INFORMA HEALTHCARE, GB LNKD- DOI:10.1517/13543776.15.3.271, vol. 15, no. 3, 1 January 2005 (2005-01-01), pages 271 - 287, XP002534885, ISSN: 1354-3776 * |
ROMAGNOLI ROMEO ET AL: "The P2X7 receptor as a therapeutic target", EXPERT OPINION ON THERAPEUTIC TARGETS,, vol. 12, no. 1, 1 April 2008 (2008-04-01), pages 647 - 661, XP009105531, ISSN: 1744-7631 * |
STEINBERG ET AL., J. BIOL. CHEM., vol. 262, 1987, pages 8884 - 8888 |
STEINBERG; SILVERSTEIN, J. BIOL. CHEM., vol. 262, 1987, pages 3118 - 3122 |
SURPRENANT ET AL., SCIENCE, vol. 272, 1996, pages 3118 - 3122 |
SURPRENANT ET AL., SCIENCE, vol. 272, 1996, pages 735 - 738 |
VIRGINIO ET AL., J. PHYSIOL., vol. 519, 1999, pages 335 - 346 |
WANG, NATURE MED, vol. 10, 2004, pages B21 - B27 |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012110190A1 (fr) | 2011-02-17 | 2012-08-23 | Affectis Pharmaceuticals Ag | Nouveaux antagonistes p2x7r et leur utilisation |
WO2012163792A1 (fr) | 2011-05-27 | 2012-12-06 | Affectis Pharmaceuticals Ag | Nouveaux antagonistes de p2x7r et leur utilisation |
WO2012163456A1 (fr) | 2011-05-27 | 2012-12-06 | Affectis Pharmaceuticals Ag | Nouveaux antagonistes de p2x7r et leur utilisation |
US9221832B2 (en) | 2011-07-22 | 2015-12-29 | Actelion Pharmaceuticals Ltd. | Heterocyclic amide derivatives as P2X7 receptor antagonists |
US9718774B2 (en) | 2012-12-12 | 2017-08-01 | Idorsia Pharmaceuticals Ltd | Indole carboxamide derivatives as P2X7 receptor antagonist |
US9556117B2 (en) | 2012-12-18 | 2017-01-31 | Actelion Pharmaceuticals Ltd. | Indole carboxamide derivatives as P2X7 receptor antagonists |
US9388198B2 (en) | 2013-01-22 | 2016-07-12 | Actelion Pharmaceuticals Ltd. | Heterocyclic amide derivatives as P2X7 receptor antagonists |
US9388197B2 (en) | 2013-01-22 | 2016-07-12 | Actelion Pharmaceuticals Ltd. | Heterocyclic amide derivatives as P2X7 receptor antagonists |
US10071167B2 (en) | 2013-05-08 | 2018-09-11 | Children's Medical Center Corporation | Method of preventing and treating type 1 diabetes, allograft rejection and lung fibrosis (by targeting the ATP/P2X7R axis) |
US11452781B2 (en) | 2013-05-08 | 2022-09-27 | Children's Medical Center Corporation | Method of preventing and treating type 1 diabetes, allograft rejection and lung fibrosis (by targeting the ATP/P2X7R axis) |
Also Published As
Publication number | Publication date |
---|---|
KR20120006547A (ko) | 2012-01-18 |
US8268861B2 (en) | 2012-09-18 |
EP2243772B1 (fr) | 2012-01-18 |
SMT201200017B (it) | 2012-07-10 |
CN102395562A (zh) | 2012-03-28 |
MX2011010810A (es) | 2012-01-12 |
US20100267762A1 (en) | 2010-10-21 |
SG175232A1 (en) | 2011-12-29 |
ES2380908T3 (es) | 2012-05-21 |
PT2243772E (pt) | 2012-03-28 |
PL2243772T3 (pl) | 2012-05-31 |
SI2243772T1 (sl) | 2012-05-31 |
US20110212992A1 (en) | 2011-09-01 |
AU2010237302A1 (en) | 2011-12-01 |
BRPI1014902A2 (pt) | 2016-04-19 |
ATE541832T1 (de) | 2012-02-15 |
JP2012523440A (ja) | 2012-10-04 |
CA2758474A1 (fr) | 2010-10-21 |
ZA201108305B (en) | 2012-08-29 |
DK2243772T3 (da) | 2012-02-13 |
HRP20120271T1 (hr) | 2012-04-30 |
US7919503B2 (en) | 2011-04-05 |
EP2243772A1 (fr) | 2010-10-27 |
EA201101479A1 (ru) | 2012-05-30 |
IL215444A0 (en) | 2011-12-29 |
CY1112758T1 (el) | 2016-02-10 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7919503B2 (en) | P2X7R antagonists and their use | |
CA2719745C (fr) | Nouveaux antagonistes de p2x7r et leur utilisation | |
WO2016041489A1 (fr) | Inhibiteur de l'indoleamine-2,3-dioxygénase et son procédé de préparation | |
AU2006257861A1 (en) | Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof | |
WO2012163792A1 (fr) | Nouveaux antagonistes de p2x7r et leur utilisation | |
JPH04506222A (ja) | N−置換複素環誘導体およびその製法 | |
ZA200500153B (en) | -3 (sulfonamidoethyl)-indole derivatives for use as glucocorticoid mimetics in the treatment of inflammatory, allergic and proliferative diseases | |
AU2011261164A1 (en) | Haematopoietic-prostaglandin D2 synthase inhibitors | |
WO2012110190A1 (fr) | Nouveaux antagonistes p2x7r et leur utilisation | |
US8815892B2 (en) | P2X7R antagonists and their use | |
WO2012163456A1 (fr) | Nouveaux antagonistes de p2x7r et leur utilisation | |
JPS63107963A (ja) | 新規なイミダゾール誘導体もしくはその塩およびそれらを含有する抗炎症剤、解熱鎮痛剤または抗関節炎剤 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 201080016692.9 Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 10707544 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2758474 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: MX/A/2011/010810 Country of ref document: MX |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2012505103 Country of ref document: JP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2010237302 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 201101479 Country of ref document: EA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 4617/KOLNP/2011 Country of ref document: IN |
|
ENP | Entry into the national phase |
Ref document number: 20117026988 Country of ref document: KR Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2010237302 Country of ref document: AU Date of ref document: 20100311 Kind code of ref document: A |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 10707544 Country of ref document: EP Kind code of ref document: A1 |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: PI1014902 Country of ref document: BR |
|
ENP | Entry into the national phase |
Ref document number: PI1014902 Country of ref document: BR Kind code of ref document: A2 Effective date: 20111010 |